Novartis, which last week was publicly shamed by the FDA for manipulating data tied to the application of its gene therapy Zolgensma, has said that it launched an investigation in March, as soon as it learned of the issue.
But records from the lab where the manipulation arose suggest that the company’s investigation may not have been as deep or wide as the Swiss drugmaker has proclaimed.
Documents referenced in a Form 483 by the FDA, which inspected the lab a month after it learned of the falsified records, also suggest the data-fudging began at least in early 2018 and could have been uncovered by managers at AveXis during several steps in the clinical outcome assessment.
Novartis has claimed that the company launched an internal probe when a scientist raised the allegations in March, and by early May had determined that scientist was correct. It didn't inform the FDA about the allegations until June 28, more than a month after Zolgensma was approved. Novartis said it needed to complete its probe before telling the FDA.
But the FDA inspection report says it found that Novartis’ gene unit AveXis didn't open a Nonconformance Report into the potentially manipulated assay tests “until 15 May 2019" even though the "initial allegation is documented as having been reported on 14 March 2019.”
The issues exploded on the scene last week when acting FDA chief Ned Sharpless, M.D., announced its investigation. The agency said it has determined that the falsification was limited to “a small portion of the product testing data that was contained in the marketing application,” and that the drug was safe and effective and should remain on the market.
But Sharpless also tweeted that the agency "will use its full authorities to take action, if appropriate, which may include civil or criminal penalties."
In a call with investors, Novartis CEO Vas Narasimhan declared the drugmaker had not tried to mislead the FDA and didn’t want to inform the agency until it knew exactly what had happened and whether the falsification put patients at risk. He said the investigation found the mismanaged data involved a potency assay Novartis no longer used in testing Zolgensma during production. Narasimhan said the Novartis' team did the “best we could."
Perhaps, but the Form 483 shows that some reports had date discrepancies noted during a historical data review on January 31, 2018. A nonconformance report also showed that that an assay "was not completed at the time of (clinical outcome assessment) generation and approval" for one lot. But the FDA says no one investigated further.
There was also a nonconformance report opened on Aug. 23, 2018 when discrepancies were found in the “data that was used to calculate relative potency for AVXS-101 Drug Product.” Then on Oct.15, 2018, another NCR was filed after inconsistencies were found in previously reported mouse survival data used to determine potentcy. A quality control employee was verbally informed about the issue but didn’t require it be documented in writing.
Other issues uncovered by inspectors included that vivarium employees who had responsibilities for manufacturing functions were reporting to an R&D scientist with no GMP experience.
The FDA has said it is continuing to investigate. Five Senate Democrats are also urging the agency to hold AveXis accountable for its “malfeasance, including through all appropriate criminal, civil and regulatory actions against the company.”
On top of that, the lawmakers are demanding Sharpless explain why the FDA decided last October to withdraw a regulation that would have required drugmakers to promptly report suspected falsified data, and whether the FDA plans to reinstate it in the wake of the AveXis case.